Project Summary With an increasing older population, including the generational aging of the baby boomers, age-related eye diseases are common and becoming more prevalent. Currently, it is estimated that 11 million Americans suffer from age-related macular degeneration (AMD) - a number that is expected to double in the next generation. The first world diabetes epidemic has also brought about a sharp rise in the number of cases of diabetic retinopathy. In the last few years, the FDA has approved two anti-VEGF proteins for the treatment of AMD. And while successful, these therapies are expensive and require regular intravitreal administration. In addition to understandable patient aversion, these treatments have a host of adverse side effects, including conjunctival hemorrhage, eye pain, vitreous floaters, increased intraocular pressure, vitreous detachment, intraocular inflammation, and even retinal detachment. Somatostatin receptors are located in the mammalian retina and early studies suggested they could be effective anti-proliferative agents for eye diseases such diabetic retinopathy and AMD. However, like the anti- VEGF proteins, the lack of blood-retinal-barrier (BRB) penetration by SST agonist peptides would require intravitreal injection, making them unattractive as drugs in this case. Our Phase I approach is to use the library from our SBIR-funded nonpeptide SST2A agonist program for acromegaly and peripheral neuroendrocrine tumors as a starting point to develop a new series of SST2A agonists capable of penetrating the BRB and accessing the tissues of the posterior eye after peripheral administration. We will use pharmacology, medicinal chemistry, physicochemical property calculation, molecular modeling, and the latest in vitro methods that mimic the tight junctions of the BRB to drive compound optimization. We will select a subset of these compounds that are likely to penetrate the BRB and will be test them in an in vivo model of plasma and ocular tissue exposure. If successful, Phase II will support the testing and optimization of these SST2A agonists in preclinical models of retinopathies, initally a laser-induced model of choroidal neovascularization, as well as begin early stage toxicological evaluation. Efficacy will be judged to understand how these peripherally-administered compounds compare to anti-VEGF therapies. We will also test whether the nonpeptides could complement the protein therapeutics, a strategy that if born out in human trials could diminish the number of intravitreal injections (and concomitant adverse effects) endured by patients. At the conclusion of Phase II, candidate compound(s) will be ready for GMP scale-up for toxicology experiments that will pave the way for human clinical trials.